Direct evidence for cytokine involvement in neointimal hyperplasia

Background-Tumor necrosis factor-alpha (TNF-alpha) and interleukin 1 (IL-1) are proximal inflammatory cytokines that stimulate expression of adhesion molecules and induce synthesis of other proinflammatory cytokines. In addit ion, TNF-alpha and IL-1 influence vascular smooth muscle cell migration and proliferation in vitro. In view of the inflammatory nature of neointimal h yperplasia (NIH), we tested the hypothesis that endogenous TNF-alpha and IL -1 modulate low shear stress-induced NIH. Methods and Results-Mice underwent unilateral common carotid artery (CCA) l igation. Low shear stress in the patent ligated CCA has previously been sho wn to result in remodeling and NIH. Reverse transcriptase-polymerase chain reaction for TNF-alpha and IL-1 alpha mRNA demonstrated both TNF-alpha and IL-1 alpha mRNA in Ligated CCAs, whereas normal and sham-operated CCAs had none. Mice lacking functional TNF-alpha (TNF-/-) developed 14-fold less neo intimal area than WT controls (P<0.05). p80 IL-1 type I receptor knockout ( IL-1RI-/-) mice tended to develop less (7-fold, P>0.05) neointimal area tha n WT controls. Furthermore, no IL-1 alpha mRNA expression was detected in C CAs from TNF-/- mice; however, TNF-alpha mRNA expression was found in the I L-1RI-/- mice. Mice that overexpress membrane-bound TNF-alpha but produce n o soluble TNF-alpha display an accentuated fibroproliferative response to l ow shear stress (P<0.05). Conclusions-These results directly demonstrate that TNF-alpha and IL-1 modu late NIH induced by low shear stress. NIH can proceed by way of soluble TNF -alpha-independent mechanisms. Specific anti-TNF-alpha and anti-IL-1 therap ies may lessen NIH.